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Cystic fibrosis causes olfactory system defects by altering progenitor cell proliferation (Bulk RNA-Seq)

ABSTRACT: A reduced sense of smell has been reported in people with cystic fibrosis (CF). These olfactory defects have largely been attributed to secondary manifestations of the disease, such as inflammation of the nasal mucosa. Here we show that CFTR, the gene responsible for CF, is expressed in proliferating olfactory human cells and that newborn CFTR null pigs display ultrastructural abnormalities in the olfactory epithelium and olfactory bulbs. In the absence of CFTR, olfactory sensory neurons still produce odor-evoked activity, but mutant animals display defective odor-guided suckling behavior after birth. Consistent with epithelial changes, we found a reduced expression of genes implicated in cell cycle and development in globose basal cells (GBCs), the neurogenic progenitor cells in the olfactory epithelium. Targeted sequencing revealed enhanced CFTR expression in the subpopulation of GBCs that is actively proliferating. Furthermore, CFTR loss caused a global reduction in the number of sensory neurons and altered olfactory receptors expression. Our findings highlight a previously unknown role of CFTR in olfactory system function by regulating progenitor cell proliferation in the olfactory epithelium.

ORGANISM(S): Sus scrofa

PROVIDER: GSE197184 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Ongoing, lifelong neurogenesis maintains the neuronal population of the olfactory epithelium in the face of piecemeal neuronal turnover and restores it following wholesale loss. The molecular phenotypes corresponding to different stages along the progression from multipotent globose basal cell (GBC) progenitor to differentiated olfactory sensory neuron are poorly characterized. We used the transgenic expression of GFP and cell surface markers to FACS-isolate Sox2-GFP(+) GBCs, Neurog1-GFP(+) GBCs and immature neurons, and OMP-GFP(+) mature neurons from normal adult mice. In addition, the latter two populations were also collected 3 weeks after olfactory bulb ablation, a lesion that results in persistently elevated neurogenesis. Global profiling of mRNA from the populations indicates that all stages of neurogenesis share a cohort of >2100 genes that are upregulated compared to sustentacular cells. A further cohort of >1200 genes are specifically upregulated in GBCs as compared to sustentacular cells and differentiated neurons. The increased rate of neurogenesis caused by olfactory bulbectomy had little effect on the transcriptional profile of the Neurog1-GFP(+) population. In contrast, the abbreviated lifespan of OMP-GFP(+) neurons born in the absence of the bulb correlated with substantial differences in gene expression as compared to the mature neurons of the normal epithelium. Detailed examination of the specific genes upregulated in the different progenitor populations revealed that the chromatin modifying complex proteins LSD1 and coREST were expressed sequentially in upstream Sox2-GFP(+) GBCs and Neurog1-GFP(+) GBCs/immature neurons. The expression patterns of these proteins are dynamically regulated after activation of the epithelium by methyl bromide lesion. Total RNA was isolated from dissected, dissociated and FACS-purified olfactory mucosal cells from normal adult mice or mice 3 weeks after unilateral bulbectomy. Cells were purified with FACS using endogenous GFP fluorescence from various transgenic lines and cell surface labeling. Two to seven adult mice were used per replicate and three replicates per condition were performed using Illumina bead arrays. 21 samples from olfactory mucosa were analyzed in this series and 3 samples were from a commercially available reference RNA sample. Universal mouse reference RNA from Stratagene was used as a general control and Normal olfactory mucosa was used as a tissue specific control.

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Cystic fibrosis causes olfactory system defects by altering progenitor cell proliferation (Bulk RNA-Seq)

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